Search

Animals have evolved innate responses to cues including social, food, and predator odors. In the natural environment, animals are faced with choices that involve balancing risk and reward where innate significance may be at odds with internal need. The ability to update the value of a cue through learning is essential for navigating changing and uncertain environments. However, the mechanisms involved in this modulation are not well defined in mammals. We have established a new olfactory assay that challenges a thirsty mouse to choose an aversive odor over an attractive odor in foraging for water, thus overriding their innate behavioral response to odor. Innately, mice prefer the attractive odor port over the aversive odor port. However, decreasing the probability of water at the attractive port leads mice to prefer the aversive port, reflecting a learned override of the innate response to the odors. The orbitofrontal cortex (OFC) is a fourth-order olfactory brain area, involved in flexible value association, with behaviorally relevant outputs throughout the limbic system. We performed optogenetic and chemogenetic silencing experiments that demonstrate the OFC is necessary for this learned modulation of innate aversion to odor. Further, we characterized odor evoked c-fos expression in learned and control mice and found significant suppression of activity in the bed nucleus of the stria terminalis, lateral septum, and central and medial amygdala. These findings reveal that the OFC is necessary for the learned override of innate behavior and may signal to limbic structures to modulate innate response to odor.

Cognitive deficits are long-lasting consequences of drug use, yet the convergent mechanism by which classes of drugs with different pharmacological properties cause similar deficits is unclear. We find that both phencyclidine and methamphetamine, despite differing in their targets in the brain, cause the same glutamatergic neurons in the medial prefrontal cortex of male mice to gain a GABAergic phenotype and decrease expression of their glutamatergic phenotype. Suppressing drug-induced gain of GABA with RNA-interference prevents appearance of memory deficits. Stimulation of dopaminergic neurons in the ventral tegmental area is necessary and sufficient to produce this gain of GABA. Drug-induced prefrontal hyperactivity drives this change in transmitter identity. Returning prefrontal activity to baseline, chemogenetically or with clozapine, reverses the change in transmitter phenotype and rescues the associated memory deficits. This work reveals a shared and reversible mechanism that regulates the appearance of cognitive deficits upon exposure to different drugs.

Anorexia nervosa (AN) is associated with food restriction and significantly low body weight, but the neurobiology of food avoidance in AN is unknown. Animal research suggests that food avoidance can be triggered by conditioned fear that engages the anterior cingulate and nucleus accumbens. We hypothesized that the neural activation during food avoidance in AN could be modeled based on aversive goal value processing. Nineteen females with AN and thirty healthy controls matched for age underwent functional magnetic resonance brain imaging while conducting a food avoidance task. During active control free-bid and computer-generated forced-bid trials, participants bid money to avoid eating food items. Brain activation was parametrically modulated with the trial-by-trial placed bids. During free-bid trials, the AN group engaged the caudate nucleus, nucleus accumbens, ventral anterior cingulate, and inferior and medial orbitofrontal cortex more than the control group. High- versus low-bid trials in the AN group were associated with higher caudate nucleus response. Emotion dysregulation and intolerance of uncertainty scores were inversely associated with nucleus accumbens free-bid trial brain response in AN. This study supports the idea that food avoidance behavior in AN involves aversive goal value computation in the nucleus accumbens, caudate nucleus, anterior cingulate, and orbitofrontal cortex.

Intracellular calcium (Ca2+) is ubiquitous to cell signaling across biology. While existing fluorescent sensors and reporters can detect activated cells with elevated Ca2+ levels, these approaches require implants to deliver light to deep tissue, precluding their noninvasive use in freely behaving animals. Here we engineered an enzyme-catalyzed approach that rapidly and biochemically tags cells with elevated Ca2+ in vivo. Ca2+-activated split-TurboID (CaST) labels activated cells within 10 min with an exogenously delivered biotin molecule. The enzymatic signal increases with Ca2+ concentration and biotin labeling time, demonstrating that CaST is a time-gated integrator of total Ca2+ activity. Furthermore, the CaST readout can be performed immediately after activity labeling, in contrast to transcriptional reporters that require hours to produce signal. These capabilities allowed us to apply CaST to tag prefrontal cortex neurons activated by psilocybin, and to correlate the CaST signal with psilocybin-induced head-twitch responses in untethered mice.

Autism spectrum disorders (ASD) can be caused by environmental factors. These factors act early in the development of the nervous system and induce stereotyped repetitive behaviors and diminished social interactions, among other outcomes. Little is known about how these behaviors are produced. In pregnant women, delivery of valproic acid (VPA) (to control seizure activity or stabilize mood) or immune activation by a virus increases the incidence of ASD in offspring. We found that either VPA or Poly Inosine:Cytosine (which mimics a viral infection), administered at mouse embryonic day 12.5, induced a neurotransmitter switch from GABA to glutamate in PV- and CCK-expressing interneurons in the medial prefrontal cortex by postnatal day 10. The switch was present for only a brief period during early postnatal development, observed in male and female mice at postnatal day 21 and reversed in both males and females by postnatal day 30. At postnatal day 90, male mice exhibited stereotyped repetitive behaviors and diminished social interaction while female mice exhibited only stereotyped repetitive behavior. Transfecting GAD1 in PV- and CCK-expressing interneurons at postnatal day 10, to reintroduce GABA expression, overrode the switch and prevented expression of autistic-like behavior. These findings point to an important role of neurotransmitter switching in mediating the environmental causes of autism.

Choosing whether to exert effort to obtain rewards is fundamental to human motivated behavior. However, the neural dynamics underlying the evaluation of reward and effort in humans is poorly understood. Here, we report an exploratory investigation into this with chronic intracranial recordings from the prefrontal cortex (PFC) and basal ganglia (BG; subthalamic nuclei and globus pallidus) in people with Parkinsons disease performing a decision-making task with offers that varied in levels of reward and physical effort required. This revealed dissociable neural signatures of reward and effort, with BG beta (12 to 20 Hz) oscillations tracking effort on a single-trial basis and PFC theta (4 to 7 Hz) signaling previous trial reward, with no effects of net subjective value. Stimulation of PFC increased overall acceptance of offers and sensitivity to reward while decreasing the impact of effort on choices. This work uncovers oscillatory mechanisms that guide fundamental decisions to exert effort for reward across BG and PFC, supports a causal role of PFC for such choices, and seeds hypotheses for future studies.

Background and aimsThe precise roles of screen media activity (SMA) and sleep problems in relation to child/adolescent psychopathology remain ambiguous. We investigated temporal relationships among sleep problems, SMA, and psychopathology and potential involvement of thalamus-prefrontal-cortex (PFC)-brainstem structural covariation.MethodsThis study utilized data from the Adolescent Brain Cognitive Development study (n = 4,641 ages 9-12) at baseline, Year1, and Year2 follow-up. Cross-Lagged Panel Models (CLPMs) investigated reciprocal predictive relationships between sleep duration/problems, SMA, and psychopathology symptoms. A potential mediating role of baseline Thalamus-PFC-brainstem covariation on SMA-externalizing relationships was examined.ResultsParticipants were divided into discovery (n = 2,359, 1,054 girls) and replication (n = 2,282, 997 girls) sets. CLPMs showed 1) bidirectional associations between sleep duration and SMA in late childhood, with higher frequency SMA predicting shorter sleep duration (β = -0.10 [95%CI: -0.16, -0.03], p = 0.004) and vice versa (β = -0.11 [95%CI: -0.18, -0.05], p < 0.001); 2) externalizing symptoms at age 10-11 predicting sleep problems (β = 0.11 [95%CI: 0.04, 0.19], p = 0.002), SMA (β = 0.07 [95%CI: 0.01, 0.13], p = 0.014), and internalizing symptoms (β = 0.09 [95%CI: 0.05, 0.13], p < 0.001) at age 11-12; and 3) externalizing behavior at age 10-11 partially mediating the relationship between baseline thalamus-PFC-brainstem covariation and SMA at age 11-12 (indirect effect = 0.032 [95%CI: 0.003, 0.067], p-value = 0.030). Findings were replicable.ConclusionWe found bi-directional SMA-sleep-duration associations in late childhood. Externalizing symptoms preceded future SMA and sleep disturbances and partially mediated relationships between structural brain covariation and SMA. The findings emphasize the need for understanding individual differences and developing and implementing integrated strategies addressing both sleep concerns and screen time to mitigate potential impacts on psychopathology.

Single administration of low-dose ketamine has both acute and sustained anti-depressant effects. Sustained effect is associated with restoration of glutamatergic synapses in medial prefrontal cortic (mFPC) neurons. Ketamine induced profound changes in a number of molecular pathways in a mouse model for chronic stress. Cell-cell communication analyses predicted that planar-cell-polarity (PCP) signaling was decreased after chronic administration of corticosterone but increased following ketamine administration in most of the excitatory neurons. Similar decrease of PCP signaling in excitatory neurons was predicted in dorsolateral prefrontal cortical (dl-PFC) neurons of patients with major depressive disorder (MDD). We showed that the basolateral amygdala (BLA)-projecting infralimbic prefrontal cortex (IL PFC) neurons regulate immobility time in the tail suspension test and food consumption. Conditionally knocking out Celsr2 and Celsr3 or Prickle2 in the BLA-projecting IL PFC neurons abolished ketamine-induced synapse restoration and behavioral remission. Therefore, PCP proteins in IL PFC-BLA neurons mediate synapse restoration induced by of low-dose ketamine.

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550,000 cell type-specific regulatory elements and >1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.

The ability to respond to emotional events in a context-sensitive and goal-oriented manner is essential for adaptive functioning. In models of behavioral and emotion regulation, the lateral prefrontal cortex (LPFC) is postulated to maintain goal-relevant representations that promote cognitive control, an idea rarely tested with causal inference. Here, we altered mid-LPFC function in healthy individuals using a putatively inhibitory brain stimulation protocol (continuous theta burst; cTBS), followed by fMRI scanning. Participants performed the Affective Go/No-Go task, which requires goal-oriented action during affective processing. We targeted mid-LPFC (vs. a Control site) based on the individualized location of action-goal representations observed during the task. cTBS to mid-LPFC reduced action-goal representations in mid-LPFC and impaired goal-oriented action, particularly during processing of negative emotional cues. During negative-cue processing, cTBS to mid-LPFC reduced functional coupling between mid-LPFC and nodes of the default mode network, including frontopolar cortex-a region thought to modulate LPFC control signals according to internal states. Collectively, these results indicate that mid-LPFC goal-relevant representations play a causal role in governing context-sensitive cognitive control during emotional processing.

BACKGROUND: Alzheimers disease (AD) is a devastating neurodegenerative disorder affecting 44 million people worldwide, leading to cognitive decline, memory loss, and significant impairment in daily functioning. The recent single-cell sequencing technology has revolutionized genetic and genomic resolution by enabling scientists to explore the diversity of gene expression patterns at the finest resolution. Most existing studies have solely focused on molecular perturbations within each cell, but cells live in microenvironments rather than in isolated entities. Here, we leveraged the large-scale and publicly available single-nucleus RNA sequencing in the human prefrontal cortex to investigate cell-to-cell communication in healthy brains and their perturbations in AD. We uniformly processed the snRNA-seq with strict QCs and labeled canonical cell types consistent with the definitions from the BRAIN Initiative Cell Census Network. From ligand and receptor gene expression, we built a high-confidence cell-to-cell communication network to investigate signaling differences between AD and healthy brains. RESULTS: Specifically, we first performed broad communication pattern analyses to highlight that biologically related cell types in normal brains rely on largely overlapping signaling networks and that the AD brain exhibits the irregular inter-mixing of cell types and signaling pathways. Secondly, we performed a more focused cell-type-centric analysis and found that excitatory neurons in AD have significantly increased their communications to inhibitory neurons, while inhibitory neurons and other non-neuronal cells globally decreased theirs to all cells. Then, we delved deeper with a signaling-centric view, showing that canonical signaling pathways CSF, TGFβ, and CX3C are significantly dysregulated in their signaling to the cell type microglia/PVM and from endothelial to neuronal cells for the WNT pathway. Finally, after extracting 23 known AD risk genes, our intracellular communication analysis revealed a strong connection of extracellular ligand genes APP, APOE, and PSEN1 to intracellular AD risk genes TREM2, ABCA1, and APP in the communication from astrocytes and microglia to neurons. CONCLUSIONS: In summary, with the novel advances in single-cell sequencing technologies, we show that cellular signaling is regulated in a cell-type-specific manner and that improper regulation of extracellular signaling genes is linked to intracellular risk genes, giving the mechanistic intra- and inter-cellular picture of AD.

Subjects are often willing to pay a cost for information. In a procedure that promotes paradoxical choices, animals choose between a richer option followed by a cue that is rewarded 50% of the time (No Info) vs. a leaner option followed by one of two cues that signal certain outcomes: one always rewarded (100%) and the other never rewarded, 0% (Info). Since decisions involve comparing the subjective value of options after integrating all their features, preference for information may rely on cortico-amygdalar circuitry. To test this, male and female rats were prepared with bilateral inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in the anterior cingulate cortex, orbitofrontal cortex, basolateral amygdala, or null virus (control). We inhibited these regions after stable preference was acquired. We found that inhibition of the anterior cingulate cortex destabilized choice preference in female rats without affecting latency to choose or response rate to cues. A logistic regression fit revealed that previous choice predicted current choice in all conditions, however previously rewarded Info trials strongly predicted preference in all conditions except in female rats following anterior cingulate cortex inhibition. The results reveal a causal, sex-dependent role for the anterior cingulate cortex in decisions involving information.

Self-agency is the awareness of being the agent of ones own thoughts and actions. Self-agency is essential for interacting with the outside world (reality-monitoring). The medial prefrontal cortex (mPFC) is thought to be one neural correlate of self-agency. We investigated whether mPFC activity can causally modulate self-agency on two different tasks of speech-monitoring and reality-monitoring. The experience of self-agency is thought to result from making reliable predictions about the expected outcomes of ones own actions. This self-prediction ability is necessary for the encoding and memory retrieval of ones own thoughts during reality-monitoring to enable accurate judgments of self-agency. This self-prediction ability is also necessary for speech-monitoring where speakers consistently compare auditory feedback (what we hear ourselves say) with what we expect to hear while speaking. In this study, 30 healthy participants are assigned to either 10 Hz repetitive transcranial magnetic stimulation (rTMS) to enhance mPFC excitability (N = 15) or 10 Hz rTMS targeting a distal temporoparietal site (N = 15). High-frequency rTMS to mPFC enhanced self-predictions during speech-monitoring that predicted improved self-agency judgments during reality-monitoring. This is the first study to provide robust evidence for mPFC underlying a causal role in self-agency, that results from the fundamental ability of improving self-predictions across two different tasks.

This study examined whether a 3-month mild-exercise intervention could improve executive function in healthy middle-aged and older adults in a randomized control trial. Ultimately, a total of 81 middle-aged and older adults were randomly assigned to either an exercise group or a control group. The exercise group received 3 months of mild cycle exercise intervention (3 sessions/week, 30-50 min/session). The control group was asked to behave as usual for the intervention period. Before and after the intervention, participants did color-word matching Stroop tasks (CWST), and Stroop interference (SI)-related reaction time (RT) was assessed as an indicator of executive function. During the CWST, prefrontal activation was monitored using functional near-infrared spectroscopy (fNIRS). SI-related oxy-Hb changes and SI-related neural efficiency (NE) scores were assessed to examine the underlying neural mechanism of the exercise intervention. Although the mild-exercise intervention significantly decreased SI-related RT, there were no significant effects of exercise intervention on SI-related oxy-Hb changes or SI-related NE scores in prefrontal subregions. Lastly, changes in the effects of mild exercise on NE with advancing age were examined. The 81 participants were divided into two subgroups (younger-aged subgroup [YA], older-aged subgroup [OA], based on median age [68 years.]). Interestingly, SI-related RT significantly decreased, and SI-related NE scores in all ROIs of the prefrontal cortex significantly increased only in the OA subgroup. These results reveal that a long-term intervention of very light-intensity exercise has a positive effect on executive function especially in older adults, possibly by increasing neural efficiency in the prefrontal cortex.

Sevoflurane, the predominant pediatric anesthetic, has been linked to neurotoxicity in young mice, although the underlying mechanisms remain unclear. This study focuses on investigating the impact of neonatal sevoflurane exposure on cell-type-specific alterations in the prefrontal cortex (PFC) of young mice. Neonatal mice were subjected to either control treatment (60% oxygen balanced with nitrogen) or sevoflurane anesthesia (3% sevoflurane in 60% oxygen balanced with nitrogen) for 2 hours on postnatal days (PNDs) 6, 8, and 10. Behavioral tests and single-nucleus RNA sequencing (snRNA-seq) of the PFC were conducted from PNDs 31 to 37. Mechanistic exploration included clustering analysis, identification of differentially expressed genes (DEGs), enrichment analyses, single-cell trajectory analysis, and genome-wide association studies (GWAS). Sevoflurane anesthesia resulted in sociability and cognition impairments in mice. Novel specific marker genes identified 8 distinct cell types in the PFC. Most DEGs between the control and sevoflurane groups were unique to specific cell types. Re-defining 15 glutamatergic neuron subclusters based on layer identity revealed their altered expression profiles. Notably, sevoflurane disrupted the trajectory from oligodendrocyte precursor cells (OPCs) to oligodendrocytes (OLs). Validation of disease-relevant candidate genes across the main cell types demonstrated their association with social dysfunction and working memory impairment. Behavioral results and snRNA-seq collectively elucidated the cellular atlas in the PFC of young male mice, providing a foundation for further mechanistic studies on developmental neurotoxicity induced by anesthesia.

Reversal learning measures the ability to form flexible associations between choice outcomes with stimuli and actions that precede them. This type of learning is thought to rely on several cortical and subcortical areas, including the highly interconnected orbitofrontal cortex (OFC) and basolateral amygdala (BLA), and is often impaired in various neuropsychiatric and substance use disorders. However, the unique contributions of these regions to stimulus- and action-based reversal learning have not been systematically compared using a chemogenetic approach particularly before and after the first reversal that introduces new uncertainty. Here, we examined the roles of ventrolateral OFC (vlOFC) and BLA during reversal learning. Male and female rats were prepared with inhibitory designer receptors exclusively activated by designer drugs targeting projection neurons in these regions and tested on a series of deterministic and probabilistic reversals during which they learned about stimulus identity or side (left or right) associated with different reward probabilities. Using a counterbalanced within-subject design, we inhibited these regions prior to reversal sessions. We assessed initial and pre-/post-reversal changes in performance to measure learning and adjustments to reversals, respectively. We found that inhibition of the ventrolateral orbitofrontal cortex (vlOFC), but not BLA, eliminated adjustments to stimulus-based reversals. Inhibition of BLA, but not vlOFC, selectively impaired action-based probabilistic reversal learning, leaving deterministic reversal learning intact. vlOFC exhibited a sex-dependent role in early adjustment to action-based reversals, but not in overall learning. These results reveal dissociable roles for BLA and vlOFC in flexible learning and highlight a more crucial role for BLA in learning meaningful changes in the reward environment.

Receiving a favor from another person may induce a negative feeling of indebtedness for the beneficiary. In this study, we explore these hidden costs by developing and validating a conceptual model of indebtedness across three studies that combine a large-scale online questionnaire, an interpersonal game, computational modeling, and neuroimaging. Our model captures how individuals perceive the altruistic and strategic intentions of the benefactor. These inferences produce distinct feelings of guilt and obligation that together comprise indebtedness and motivate reciprocity. Perceived altruistic intentions convey care and communal concern and are associated with activity in insula, ventromedial prefrontal cortex and dorsolateral prefrontal cortex, while inferred strategic intentions convey expectations of future reciprocity and are associated with activation in temporal parietal junction and dorsomedial prefrontal cortex. We further develop a neural utility model of indebtedness using multivariate patterns of brain activity that captures the tradeoff between these feelings and reliably predicts reciprocity behavior.

Animals, including humans, rely on contextual information to interpret ambiguous stimuli. Impaired context processing is a hallmark of several neuropsychiatric disorders, including schizophrenia, autism spectrum disorders, post-traumatic stress disorder, and addiction. While sex differences in the prevalence and manifestations of these disorders are well established, potential sex differences in context processing remain uncertain. Here, we examined sex differences in the contextual control over cue-evoked reward seeking and its neural correlates, in rats. Male and female rats were trained in a bidirectional occasion-setting preparation in which the validity of two auditory reward-predictive cues was informed by the presence, or absence, of a visual contextual feature (LIGHT: X+/DARK: X-/LIGHT: Y-/DARK: Y+). Females were significantly slower to acquire contextual control over cue-evoked reward seeking. However, once established, the contextual control over behavior was more robust in female rats; it showed less within-session variability (less influence of prior reward) and greater resistance to acute stress. This superior contextual control achieved by females was accompanied by an increased activation of the orbitofrontal cortex (OFC) compared to males. Critically, these behavioral and neural sex differences were specific to the contextual modulation process and not observed in simple, context-independent, reward prediction tasks. These results indicate a sex-biased trade-off between the speed of acquisition and the robustness of performance in the contextual modulation of cued reward seeking. The different distribution of sexes along the fast learning ↔ steady performance continuum might reflect different levels of engagement of the OFC, and might have implications for our understanding of sex differences in psychiatric disorders.

Sensory over-responsivity (SOR) is a prevalent cross-diagnostic condition that is often associated with anxiety. The biological mechanisms underlying the co-occurrence of SOR and anxiety symptoms are not well understood, despite having important implications for targeted intervention. We therefore investigated the unique associations of SOR and anxiety symptoms with physiological and neural responses to sensory stimulation for youth with anxiety disorders (ANX), autism spectrum disorder (ASD), or typical development (TD). Age/IQ-matched youth aged 8-18 years (22 ANX; 30 ASD; 22 TD) experienced mildly aversive tactile and auditory stimuli during functional magnetic resonance imaging and then during skin conductance response (SCR) and heart rate (HR) measurements. Caregivers reported on participants' SOR and anxiety symptoms. ASD/ANX youth had elevated SOR and anxiety symptoms compared to TD. ASD/ANX youth showed similar, heightened brain responses to sensory stimulation compared to TD youth, but brain responses were more highly related to SOR symptoms in ASD youth and to anxiety symptoms in ANX youth. Across ASD/ANX youth, anxiety symptoms uniquely related to greater SCR whereas SOR uniquely related to greater HR responses to sensory stimulation. Behavioral and neurobiological over-responsivity to sensory stimulation was shared across diagnostic groups. However, findings support SOR and anxiety as distinct symptoms with unique biological mechanisms, and with different relationships to neural over-reactivity dependent on diagnostic group. Results indicate a need for targeted treatment approaches.

• Chronic pain methylates genes in the prefrontal cortex that cause both pain and cognitive dysfunction in mouse knockout experiments. • Chronic pain-induced methylation specifically targets genes associated with cognitive fluidity and memory in humans. • Cortical methylation in response to pain affects gene networks relevant to clinical and neuropathologic features of Alzheimer's disease. • Chronic pain and Alzheimer's disease converge onto microglia signaling pathways. Chronic pain is prevalent among aging adults. Epidemiologic evidence has demonstrated that individuals with chronic pain have accelerated memory decline and increased probability of dementia. Neurophysiologic, molecular, and pharmacologic hypotheses have been proposed to explain the relationship between chronic pain and cognitive decline, but there remains currently limited evidence supporting any of these. Here, we integrate multi-omic data across human cohorts and rodent species and demonstrate that methylation in the prefrontal cortex induced by chronic pain specifically targets transcriptional networks associated with cognitive ability, memory, and Alzheimer's disease in humans. We validate this with multiple independent data sets and identify cortical microglia as a likely mechanism by which chronic pain can increase dementia risk. Our analyses support the molecular hypothesis for the role of chronic pain in cognitive decline and identifies several potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Psychedelics hold promise as alternate treatments for neuropsychiatric disorders. However, the neural mechanisms by which they drive adaptive behavioral effects remain unclear. We isolated the specific neurons modulated by a psychedelic to determine their role in driving behavior. Using a light- and calcium-dependent activity integrator, we genetically tagged psychedelic-responsive neurons in the medial prefrontal cortex (mPFC) of mice. Single-nucleus RNA sequencing revealed that the psychedelic drove network-level activation of multiple cell types beyond just those expressing 5-hydroxytryptamine 2A receptors. We labeled psychedelic-responsive mPFC neurons with an excitatory channelrhodopsin to enable their targeted manipulation. We found that reactivation of these cells recapitulated the anxiolytic effects of the psychedelic without driving its hallucinogenic-like effects. These findings reveal essential insight into the cell-type-specific mechanisms underlying psychedelic-induced behavioral states. [ABSTRACT FROM AUTHOR]

Background: Small artery occlusion (SAO) is a common ischemic stroke subtype. However, its clinical outcome can be more severe than commonly understood. The severity of SAO can vary, ranging from mild to moderate. Iron deposition has been associated with the development and progression of stroke. However, its specific distribution and relationship with stroke severity in SAO remain unclear. The study's purpose is to investigate the differences in iron deposition between mild stroke with SAO (SAO-MiS) and moderate stroke with SAO (SAO-MoS) through quantitative susceptibility mapping (QSM) and its association with neurological deficits. Methods: Sixty-eight SAO participants within 24 hours of first onset were enrolled and separated into SAO-MiS and SAO-MoS according to the National Institutes of Health Stroke Scale (NIHSS) scores. QSM helped calculate the susceptibility maps, reflecting the iron content within the brain. The susceptibility maps were analyzed using voxel-wise statistical analysis to compare the iron deposition between SAO-MiS and SAO-MoS. Then, differentially distributed iron deposition helped differentiate between mild and moderate stroke using support vector machine (SVM) methods. Results: Compared with SAO-MiS, SAO-MoS depicted elevated iron deposition in the left pallidum, parahippocampal gyrus, and superior frontal gyrus medial region, and is lower in the right superior/middle frontal gyrus and bilateral supplementary motor area. Based on iron deposition, the SVM classifier's analysis revealed a high power to discriminate SAO-MoS from SAO-MiS. In addition, fibrinogen, triglyceride (TG), and total cholesterol (TC) were linked with QSM values in specific brain regions. Conclusions: Our study first revealed the brain iron distribution after SAO and differently distributed iron deposition in SAO-MiS and SAO-MoS. The results indicate that iron deposition could play a role in the pathophysiology of SAO and its correlation with stroke severity. [ABSTRACT FROM AUTHOR]

Although there are a few first-line treatment options for bipolar depression, none are rapid-acting. A new rTMS protocol, Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT®), has been shown to have a rapid antidepressant effect in major depressive disorder (MDD). We examined the preliminary safety, tolerability, and efficacy of SAINT for the treatment of depression in a small sample of persons with treatment-resistant bipolar I disorder. Participants with treatment-resistant bipolar I disorder currently experiencing moderate to severe depression were treated with open-label SAINT. Resting-state functional MRI (fMRI) was used to generate individualized treatment targets for each participant based on the region of the left dorsolateral prefrontal cortex most anticorrelated with the subgenual anterior cingulate cortex. Participants were treated with 10 iTBS sessions daily, with 50-min intersession intervals, for up to 5 consecutive days. The primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to immediate follow-up after treatment. We treated 10 participants and found a mean reduction of 16.9 in MADRS scores, with a 50 % response rate and 40 % remission rate immediately following treatment. 60 % of participants met remission criteria within the 1-month period following treatment. No serious adverse events, manic episodes, or cognitive side effects were observed. Our study has a limited sample size and larger samples are needed to confirm safety and efficacy. SAINT has shown preliminary feasibility, safety, tolerability, and efficacy in treating treatment-resistant bipolar I depression. Double-blinded sham-controlled trials with larger samples are needed to confirm safety and efficacy. • A novel TMS protocol, SAINT, showed rapid antidepressant effect in bipolar I patients. • Stanford-developed, SAINT, was successfully used at two other academic hospitals. • No signs of mania or negative cognitive side effects were observed. [ABSTRACT FROM AUTHOR]

Depression is a significant public health concern. Identifying biopsychosocial risk factors for depression is important for developing targeted prevention. Studies have demonstrated that blunted striatal activation during reward processing is a risk factor for depression; however, few have prospectively examined whether adolescent reward-related resting-state functional connectivity (rsFC) predicts depression symptoms in adulthood and how this relates to known risk factors (e.g., childhood trauma). At baseline, 66 adolescents (mean age = 14.7, SD = 1.4, 68 % female) underwent rsFC magnetic resonance imaging and completed the Children's Depression Inventory (CDI). At follow-up (mean time between adolescent scan and adult follow-up = 10.1 years, SD = 1.6, mean adult age = 24.8 years, SD = 1.7), participants completed the Childhood Trauma Questionnaire (CTQ) and Beck Depression Inventory– Second Edition (BDI-2). Average rsFC was calculated between nodes in mesocorticolimbic reward circuitry: ventral striatum (VS), rostral anterior cingulate cortex (rACC), medial orbitofrontal cortex, and ventral tegmental area. Linear regressions assessed associations between rsFC, BDI-2, and CTQ, controlling for adolescent CDI, sex assigned at birth, and scan age (Bonferroni corrected). Greater childhood trauma was associated with higher adulthood depression symptoms. Stronger VS-rACC rsFC during adolescence was associated with greater depression symptoms in adulthood and greater childhood trauma. The small sample size, limited depression severity, and seed-based approach are limitations. The associations between adolescent striatal-cingulate rsFC and childhood trauma and adult depression symptoms suggest this connectivity may be an early neurobiological risk factor for depression and that early life experience plays an important role. Increased VS-rACC connectivity may represent an over-regulatory response on the striatum, commonly reported in depression, and warrants further investigation. • Depression rates are rising and childhood trauma is a risk factor for depression. • Trauma-exposed and depressed populations show reward-related neural aberrations. • Adolescent reward-related neural aberrations were related to adulthood depression. • Childhood trauma was associated with the same adolescent neural aberrations. • Further investigation of biopsychosocial risk factors of depression is needed. [ABSTRACT FROM AUTHOR]

The prefrontal cortex is critical for decision-making across species, with its activity linked to choosing between options. Drift diffusion models (DDMs) are commonly employed to understand the neural computations underlying this behavior. Studies exploring the specific roles of regions of the rodent prefrontal cortex in controlling the decision process are limited. This study explored the role of the prelimbic cortex (PLC) in decision-making using a two-alternative forced-choice task. Rats first learned to report the location of a lateralized visual stimulus. The brightness of the stimulus indicated its reward value. Then, the rats learned to make choices between pairs of stimuli. Sex differences in learning were observed, with females responding faster and more selectively to high-value stimuli than males. DDM analysis found that males had decreased decision thresholds during initial learning, whereas females maintained a consistently higher drift rate. Pharmacological manipulations revealed that PLC inactivation reduced the decision threshold for all rats, indicating that less information was needed to make a choice in the absence of normal PLC processing. μ-Opioid receptor stimulation of the PLC had the opposite effect, raising the decision threshold and reducing bias in the decision process toward high-value stimuli. These effects were observed without any impact on the rats' choice preferences. Our findings suggest that PLC has an inhibitory role in the decision process and regulates the amount of evidence that is required tomake a choice. That is, PLC activity controls "when," but not "how," to act. [ABSTRACT FROM AUTHOR]

Basolateral amygdala (BLA) neurons are engaged by emotionally salient stimuli. An area of increasing interest is how BLA dynamics relate to evolving reward-seeking behavior, especially under situations of uncertainty or ambiguity. Here, we recorded the activity of individual BLA neurons in male rats across the acquisition and extinction of conditioned reward seeking. We assessed ongoing neural dynamics in a task where long reward cue presentations preceded an unpredictable, variably time reward delivery. We found that, with training, BLA neurons discriminated the CS+ and CS- cues with sustained cue-evoked activity that correlated with behavior and terminated only after reward receipt. BLA neurons were bidirectionally modulated, with a majority showing prolonged inhibition during cued reward seeking. Strikingly, population-level analyses revealed that neurons showing cue-evoked inhibitions and those showing excitations similarly represented the CS+ and behavioral state. This sustained population code rapidly extinguished in parallel with conditioned behavior. We next assessed the contribution of the orbitofrontal cortex (OFC), amajor reciprocal partner to the BLA. Inactivation of the OFC while simultaneously recording in the BLA revealed a blunting of sustained cue-evoked activity in the BLA that accompanied reduced reward seeking. Optogenetic disruption of BLA activity and OFC terminals in the BLA also reduced reward seeking. Our data indicate that the BLA represents reward-seeking states via sustained, bidirectional cue-driven neural encoding. This code is regulated by cortical input and is important for the maintenance of vigilant reward-seeking behavior. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) utilizes radiotracers like [18F]fluorodeoxyglucose (FDG) to measure brain activity in health and disease. Performing behavioral tasks between the FDG injection and the PET scan allows the FDG signal to reflect task-related brain networks. Building on this principle, we introduce an approach called behavioral task–associated PET (beta-PET) consisting of two scans: the first after a mouse is familiarized with a conditioning chamber, and the second upon recall of contextual threat. Associative threat conditioning occurs between scans. Beta-PET focuses on brain regions encoding threat memory (e.g., amygdala, prefrontal cortex) and contextual aspects (e.g., hippocampus, subiculum, entorhinal cortex). Our results show that beta-PET identifies a biologically defined network encoding contextual threat memory and its uncoupling in a mouse model of long sepsis. Moreover, machine learning algorithms (linear logistic regression) and ordinal trends analysis demonstrate that beta-PET robustly predicts the behavioral defense response and its breakdown during long sepsis. [ABSTRACT FROM AUTHOR]

How consciousness is lost in states such as sleep or anesthesia remains a mystery. To gain insight into this phenomenon, concurrent recordings of electrophysiology signals in the anterior cingulate cortex and whole‐brain functional magnetic resonance imaging (fMRI) are conducted in rats exposed to graded propofol, undergoing the transition from consciousness to unconsciousness. The results reveal that upon the loss of consciousness (LOC), there is a sharp increase in low‐frequency power of the electrophysiological signal. Additionally, fMRI signals exhibit a cascade of deactivation across a pathway including the hippocampus, thalamus, and medial prefrontal cortex (mPFC) surrounding the moment of LOC, followed by a broader increase in brain activity across the cortex during sustained unconsciousness. Furthermore, sliding window analysis demonstrates a temporary increase in synchrony of fMRI signals across the hippocampus‐thalamus‐mPFC pathway preceding LOC. These data suggest that LOC may be triggered by sequential activities in the hippocampus, thalamus, and mPFC, while wide‐spread activity increases in other cortical regions commonly observed during anesthesia‐induced unconsciousness may be a consequence, rather than a cause of LOC. Taken together, the study identifies a cascade of neural events unfolding as the brain transitions into unconsciousness, offering insight into the systems‐level neural mechanisms underpinning LOC. [ABSTRACT FROM AUTHOR]

Aims: We aimed to investigate the anxiolytic effect of darbepoetin alpha (DEPO), an erythropoietin derivative, in a neuroinflammation model regarding different behaviors and biological pathways. Methods: Forty adult male Wistar albino rats were divided into four groups (control, LPS, DEPO, and DEPO + LPS). The rats were treated with 5 µg /kg DEPO once a week for four weeks, after which neuroinflammation was induced with 2 mg/kg lipopolysaccharide (LPS). The elevated plus maze, open-field, and light‒dark box tests were conducted to assess anxiety levels. Harderian gland secretions were scored via observation. Tumor necrosis factor alpha (TNF-α), Interleukin-1-beta (IL-1β), brain-derived growth factor (BDNF), serotonin, cortisol, total antioxidant/oxidant (TAS/TOS), and total/free thiol levels were measured in the prefrontal cortex, striatum, and serum. Results: DEPO had a potent anxiolytic effect on both DEPO and DEPO + LPS groups. Compared to the control group, DEPO administration caused an increase in serotonin and BDNF levels and decreased basal cortisol and TNF-α levels in naive rats. IL-1β did not alter after DEPO administration in naive rats. Prophylactic DEPO treatment remarkably downregulated cortisol, IL-1β, and TNF-α in the DEPO + LPS group. In addition, prophylactic DEPO administration significantly attenuated the decrease in serotonin and BDNF levels in the DEPO + LPS group. Furthermore, DEPO ameliorated excessive harderian gland secretion in the DEPO + LPS group. Compared with those in the control group, the free thiol content in the serum increased after DEPO administration. No similar effect was seen in the DEPO + LPS group receiving prophylactic DEPO. TAS showed no difference among all experimental groups. DEPO administration increased TOS and OSI in the serum and prefrontal cortex but not in the striatum. This effect was not seen in the DEPO + LPS group. Conclusion: Darbepoetin alpha had an anxiolytic effect on many physiological mechanisms in a neuroinflammation model and naive rats. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion Methamphetamine use disorders (MUDs) cause widespread disruptions in metabolomic and immunologic processes, highlighting the need for new therapeutic approaches. The purpose of this study was to find molecular and neuroimaging biomarkers for methamphetamine addiction.In this study, we recruited 231 patients with MUD at varying stages of withdrawal and 40 healthy controls to quantify the blood levels of 52 molecules using enzyme‐linked immunosorbent assay.The overall molecular disruption caused by methamphetamine was inversely related to withdrawal time (P = 0.0008), with partial recovery observed after 1 year of follow‐up (P = 2.20 × 10−5). Molecules related to stress, immune activation, oxidative products, and cardiac injury were significantly elevated in all MUD groups, while antioxidation enzymes were downregulated. Additionally, the blood level of brain‐derived neurotrophic factor was significantly correlated with gray matter volumes in nine brain regions (fusiform gyrus, orbitofrontal cortex, temporal pole, caudate, cerebellum crus, and vermis, adjusted P < 0.05) among patients with MUD.These findings suggest that patients with MUD exhibit elevated levels of immune response, stress, and oxidative stress, which are associated with brain structural abnormalities. [ABSTRACT FROM AUTHOR]

• Snf7-3 KO mice reveal its role in synaptic function and cognitive processing. • Snf7-3 KO mice show age-dependent social recognition deficits and higher mEPSCs. • Conditional Snf7-3 KO causes early cognitive deficits and synaptic hyperactivity. • Snf7-3 deficiency increases pre- and postsynaptic puncta in hippocampal neurons. • Snf7-3 is crucial for synaptic maintenance and may contribute to neurodegeneration. Snf7-3 is a crucial component of the endosomal sorting complexes required for transport (ESCRT) pathway, playing a vital role in endolysosomal functions. To elucidate the role of Snf7-3 in vivo, we developed conventional-like and conditional Snf7-3 knockout (KO) mouse models using a "Knockout-first" strategy. Conventional-like Snf7-3 KO mice showed significantly reduced Snf7-3 mRNA expression, and older mice (25–40 weeks) exhibited impaired social recognition and increased miniature excitatory postsynaptic currents (mEPSCs). Similarly, conditional KO mice aged 8–24 weeks, with Snf7-3 specifically deleted in forebrain excitatory neurons, displayed impaired object location memory and elevated mEPSC frequency. Consistently, Snf7-3 knockdown in cultured mouse hippocampal neurons led to increased densities of pre- and postsynaptic puncta, supporting the observed increase in mEPSC frequency. In addition, enhanced dendritic complexity was observed in the medial prefrontal cortex of these mice, indicating early synaptic disturbances. Our findings underscore the critical role of Snf7-3 in maintaining normal cognitive functions and social behaviors. The observed synaptic and behavioral deficits in both conventional-like and conditional KO mice highlight the importance of Snf7-3 in specific neuronal populations, suggesting that early synaptic changes could precede more pronounced cognitive impairments. [ABSTRACT FROM AUTHOR]

Different brain areas have distinct roles in the processing and regulation of pain and thus may form specific pharmacological targets. Prior research has shown that AMPAkines, a class of drugs that increase glutamate signaling, can enhance descending inhibition from the prefrontal cortex (PFC) and nucleus accumbens. On the other hand, activation of neurons in the anterior cingulate cortex (ACC) is known to produce the aversive component of pain. The impact of AMPAkines on ACC, however, is not known. We found that direct delivery of CX516, a well-known AMPAkine, into the ACC had no effect on the aversive response to pain in rats. Furthermore, AMPAkines did not modulate the nociceptive response of ACC neurons. In contrast, AMPAkine delivery into the prelimbic region of the prefrontal cortex (PL) reduced pain aversion. These results indicate that the analgesic effects of AMPAkines in the cortex are likely mediated by the PFC but not the ACC. [ABSTRACT FROM AUTHOR]

Background: The hypothalamus has been recognized as a core structure in the sleep-wake cycle. However, whether the neuroplasticity of the hypothalamus is involved in the acupuncture treatment of insomnia remains elusive. Methods: We recruited 42 patients with chronic insomnia disorder (CID) and 23 matched healthy controls (HCs), with CID patients randomly assigned to receive real acupuncture (RA) or sham acupuncture (SA) for four weeks. Insomnia severity was evaluated using the Pittsburgh Sleep Quality Index (PSQI) score, and the resting-state functional connectivity (rsFC) of the hypothalamus was assessed via functional magnetic resonance imaging (fMRI). Results: In the cross-sectional investigation, CID patients showed increased rsFC between the medial hypothalamus (MH) and left lateral orbital frontal cortex (LOFC), and bilateral medial orbital frontal cortex (MOFC) compared to HCs. In the longitudinal experiment, PSQI scores significantly decreased in the RA group (p = 0.03) but not in the SA group. Interestingly, the increased MH-LOFC connectivity was found to be reduced following RA treatment. In addition, the altered rsFC of MH-LOFC significantly correlated with clinical improvement in the RA group (r = -0.692, p = 0.006). Conclusion: This randomized neuroimaging study provides preliminary evidence that acupuncture may improve insomnia symptoms by restoring circuits associated with hypothalamic subregions. Trial registration: This trial has been registered on the Chinese Clinical Trial Registry (www.chictr.org.cn) with the identifier (ChiCTR1800017092). Registered date: 11/07/2018. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) is generally considered to have a high risk of progression to Alzheimer's disease. Our study aimed to investigate the abnormal functional connectivity (FC) in prefrontal cortex (PFC) in patients with MCI and explore the relationship between the observed changes and cognitive function. Methods: Sixty-seven patients with MCI and 71 healthy individuals were recruited for this study. All participants underwent the Montreal Cognitive Assessment (MoCA) and functional near-infrared spectroscopy (fNIRS) examinations. Results: Compared with healthy controls (HC), the patients with MCI exhibited significantly lower MoCA scores (p < 0.001). Through FC analysis, an enhanced subnetwork was observed in the right prefrontal cortex of the MCI group, covering four pairs of channel connections: CH12-CH15, CH12-CH16, CH13-CH15, and CH13-CH16. Moreover, the FC values of these four channel pairs and the education duration were significantly correlated with MoCA scores. Subsequently, a multiple linear regression model was performed to observe the independent factors of cognition decline, serving the education duration and the average FC values of subnetwork as independent variables and the MoCA scores as the dependent variable. The regression model showed a total of 25.7% explanation power (adjusted R2 = 0.257, F = 24.723, p < 0.001). Conclusion: Our study suggested that the enhanced subnetwork within the right PFC may be involved in the pathophysiology of MCI and serve as a potential target for the treatment of MCI. [ABSTRACT FROM AUTHOR]

Introduction: This study explored the effects of task-switching type and sex on the task-switching ability of methamphetamine abstainers, as well as the differences in brain mechanisms under drug cravings under drug cravings using near-infrared spectroscopy. Methods: Craving-inducing videos were used to arouse 20 methamphetamine abstainers (including 10 men), whose switching ability was then assessed using voluntary and cued task-switching exercises. Results: During task-switching under methamphetamine cravings, the activation of the premotor cortex (PMC), supplementary motor area (SMA), frontal eye field (FEF), and dorsolateral prefrontal cortex (DLPFC) in women was significantly stronger than in men, while the activation of FEF in men was significantly stronger than in women. Voluntary task-switching induced stronger FEF activation than cued task-switching. During the latter, women exhibited stronger activation in the anterior prefrontal cortex (aPFC) than men. Discussion: Both men and women showed brain lateralization during task-switching under methamphetamine cravings. Men tended to adopt proactive control and use a top-down dominant strategy to start a new task. Women, however, tend to use a bottom-up strategy focusing on inhibiting old tasks and emotional switching. Moreover, in cued task-switching, the result shows women paid more attention to emotional processing than did men, which suggests that different task-switching training programs should be developed according to sex. [ABSTRACT FROM AUTHOR]

Background: Auditory verbal hallucinations (AVHs) are one of the signature positive symptoms of schizophrenia, affecting a substantial portion of patients with schizophrenia. These hallucinations seriously impact the lives of patients, resulting in a substantial social burden. Recent studies have shown a significant correlation between abnormal local brain activity and the neurobiological mechanisms of AVHs. However, it is not fully clear whether altered intrinsic brain activity in schizophrenia patients with AVHs is correlated with specific neurotransmitter systems. Methods: We included 50 first-episode, drug-naïve schizophrenia patients with AVHs, 50 patients without AVHs (NAVHs), and 50 age- and sex-matched healthy controls (HCs). The amplitude of low-frequency fluctuation (ALFF) was utilized to explore the altered intrinsic brain activity in the AVH group. Subsequently, we spatially correlated the altered ALFF with neurotransmitter maps using JuSpace. Results: In our study, compared to HCs, the AVH group exhibited significantly reduced ALFF in multiple brain regions, mainly including the left precuneus, bilateral supplementary motor areas, bilateral paracentral lobules, bilateral precentral gyri, and bilateral postcentral gyri. The NAVH group showed significantly reduced ALFF in the left inferior occipital gyrus, left calcarine gyrus, and left lingual gyrus compared to HCs. Furthermore, the AVH group showed higher ALFF in the right inferior frontal gyrus compared to the NAVH group. Additionally, these ALFF alterations in the AVH group were closely related to three neurotransmitters, including dopamine, serotonin and norepinephrine. Conclusion: We link neurotransmitters to abnormal intrinsic brain activity in first-episode, drug-naïve schizophrenia patients with AVHs, contributing to a comprehensive understanding of the pathophysiological processes and treatment pathways underlying AVHs. [ABSTRACT FROM AUTHOR]

The modulation of social cognition is suggested as a possible mechanism contributing to the potential clinical efficacy of psychedelics in disorders involving socio-emotional and reward processing deficits. Resting-state functional Magnetic Resonance Imaging (rs-fMRI) can be used to detect changes in brain connectivity during psychedelic-induced states. Thus, this pharmacoimaging study investigates the effects of N,N-Dimethyltryptamine (DMT) on functional connectivity in brain areas relevant to social cognition, using a within-subject design in eleven healthy experienced users. The study included both an active and a control condition, conducted at different time points. The active condition involved DMT inhalation, while the control condition did not. Seed-based connectivity was measured for the two core regions involved in theory of mind and emotional processing, respectively, the posterior supramarginal gyrus and the amygdala. DMT increased supramarginal gyrus connectivity with the precuneus, posterior cingulate gyrus, amygdala, and orbitofrontal cortex. Additionally, increased connectivity emerged between the amygdala and orbitofrontal cortex. These results demonstrate that DMT modulates brain connectivity in socio-emotional and affective-value circuits, advancing our understanding of the neural mechanisms underlying the psychedelic experience and its potential therapeutic action. [ABSTRACT FROM AUTHOR]

Spatially heterogeneous synapse loss is a characteristic of many psychiatric and neurological disorders, but the underlying mechanisms are unclear. Here, we show that spatially-restricted complement activation mediates stress-induced heterogeneous microglia activation and synapse loss localized to the upper layers of the medial prefrontal cortex (mPFC) in male mice. Single cell RNA sequencing also reveals a stress-associated microglia state marked by high expression of the apolipoprotein E gene (Apoehigh) localized to the upper layers of the mPFC. Mice lacking complement component C3 are protected from stress-induced layer-specific synapse loss, and the Apoehigh microglia population is markedly reduced in the mPFC of these mice. Furthermore, C3 knockout mice are also resilient to stress-induced anhedonia and working memory behavioral deficits. Our findings suggest that region-specific complement and microglia activation can contribute to the disease-specific spatially restricted patterns of synapse loss and clinical symptoms found in many brain diseases. Synapse loss is central to the pathogenesis of stress-related disorders. Here, the authors show that targeted synapse removal by microglia and complement during stress contributes to the effects of stress on behavior. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) is a growing concern among older adults, with limited effective pharmacological treatments available. Despite the potential of herbal medicine and acupuncture in managing MCI, there is a lack of research on their long-term effects on cognitive function and brain activity in clinical practice settings. This study aimed to address this gap by exploring the effects of a community-based program integrating herbal medicine and acupuncture on cognitive function and neural responses in older individuals with MCI. Methods: Nineteen individuals were enrolled from a pool of 250 individuals registered in the 2021 Busan Dementia Prevention & Care Program. Participants with MCI received herbal medicine, acupuncture, and pharmacopuncture treatments over a 6-month period. The Montreal Cognitive Assessment (MoCA) was administered at baseline and after 3 and 6 months to evaluate cognitive function. Functional near-infrared spectroscopy (fNIRS) was used to measure prefrontal cortex activity during cognitive task performance, including verbal fluency, Stroop color and word, and digit span backward tests. Results: Seventeen participants (13 female; mean age, 69.5 years) with MCI completed the study. Following the 6-month intervention, they exhibited a significant increase in the MoCA total score over time [F(2.32) =10.59, p < 0.0001]. Additionally, the deoxygenated hemoglobin beta coefficient in the left frontopolar prefrontal cortex significantly decreased during the Stroop task after the intervention. Conclusion: The Dementia Prevention & Care Program, which integrates herbal medicine and acupuncture, may enhance cognitive function in individuals with MCI. Moreover, the observed changes in prefrontal cortex activity after completion of the program suggest a need for further investigation of the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Words offer a unique opportunity to separate the processing mechanisms of object subcomponents from those of the whole object, because the phonological or semantic information provided by the word subcomponents (i.e., sublexical information) can conflict with that provided by the whole word (i.e., lexical information). Previous studies have revealed some of the specific brain regions and temporal information involved in sublexical information processing. However, a comprehensive spatiotemporal neural network for sublexical processing remains to be fully elucidated due to the low temporal or spatial resolutions of previous neuroimaging studies. In this study, we recorded stereoelectroencephalography signals with high spatial and temporal resolutions from a large sample of 39 epilepsy patients (both sexes) during a Chinese character oral reading task. We explored the activated brain regions and their connectivity related to three sublexical effects: phonological regularity (whether the whole character's pronunciation aligns with its phonetic radical), phonological consistency (whether characters with the same phonetic radical share the same pronunciation), and semantic transparency (whether the whole character's meaning aligns with its semantic radical). The results revealed that sublexical effects existed in the inferior frontal gyrus, precentral and postcentral gyri, temporal lobe, and middle occipital gyrus. Additionally, connectivity from the middle occipital gyrus to the postcentral gyrus and from postcentral gyrus to the fusiform gyrus was associated with the sublexical effects. These findings provide valuable insights into the spatiotemporal dynamics of sublexical processing and object recognition in the brain. [ABSTRACT FROM AUTHOR]

Estimating the direction of functional connectivity (FC) can help further elucidate complex brain function. However, the estimation of directed FC at the voxel level in fMRI data, and evaluating its performance, has yet to be done. We therefore developed a novel directed seed-based connectivity analysis (SCA) method based on normalized pairwise Granger causality that provides greater detail and accuracy over ROI-based methods. We evaluated its performance against 145 cortical retrograde tracer injections in male and female marmosets that were used as ground truth cellular connectivity on a voxel-by-voxel basis. The receiver operating characteristic (ROC) curve was calculated for each injection, and we achieved area under the ROC curve of 0.95 for undirected and 0.942 for directed SCA in the case of high cell count threshold. This indicates that SCA can reliably estimate the strong cellular connections between voxels in fMRI data. We then used our directed SCA method to analyze the human default mode network (DMN) and found that dlPFC (dorsolateral prefrontal cortex) and temporal lobe were separated from other DMN regions, forming part of the languagenetwork that works together with the core DMN regions. We also found that the cerebellum (Crus I-II) was strongly targeted by the posterior parietal cortices and dlPFC, but reciprocal connections were not observed. Thus, the cerebellum may not be a part of, but instead a target of, the DMN and language-network. Summarily, our novel directed SCA method, visualized with a new functional flat mapping technique, opens a new paradigm for whole-brain functional analysis. [ABSTRACT FROM AUTHOR]

In many jurisdictions, the criminal responsibility of adults is demarcated from pre-adults (adolescents, pre-adolescents, and children) based on a threshold criterion – one is either an adult or a pre-adult, and different levels of responsibility are accordingly inferred and imputed. But in a world where complexity is growingly acknowledged, and by that token, nuance and variety, there has been a predilection for the spectrum over the binary – or the scalar over the threshold. In the context of juvenile justice, this has manifested in a move away from the binary demarcation between adults and pre-adults through a growing faith in brain developmental science, which in turn, focuses on the developmental stages of the prefrontal cortex (PFC). In pre-adults, especially in adolescents, immature PFCs account for impulsiveness, volatility, and influence by peers, which in turn impact judgment and decision-making. These findings have been introduced in a few state and federal US courts trying juveniles, and recently, in the ICC trial and appeal of Dominic Ongwen, a child soldier. This paper assesses the nature, scope, and treatment of neuroscientific evidence, and lays down guidelines about its anticipated application in international trials involving vulnerable perpetrators such as juveniles. [ABSTRACT FROM AUTHOR]

Here, we tested the respective contributions of primate premotor and prefrontal cortex to support vocal behavior. We applied a model-based generalized linear model (GLM) analysis that better accounts for the inherent variance in natural, continuous behaviors to characterize the activity of neurons throughout the frontal cortex as freely moving marmosets engaged in conversational exchanges. While analyses revealed functional clusters of neural activity related to the different processes involved in the vocal behavior, these clusters did not map to subfields of prefrontal or premotor cortex, as has been observed in more conventional task-based paradigms. Our results suggest a distributed functional organization for the myriad neural mechanisms underlying natural social interactions and have implications for our concepts of the role that frontal cortex plays in governing ethological behaviors in primates. • Neurons in marmoset monkey PFC and PMC recorded during natural conversations • GLM and PSTH were applied to quantify neural activity in continuous behavior • Model-based approach robustly outperformed more traditional analyses • Neurons in behavior-related functional clusters were distributed throughout PFC/PMC Li and colleagues applied model-based and traditional analyses to characterize single-neuron responses in the frontal cortex while marmosets engaged in their natural conversational exchanges. Results showed that the population supported nearly all facets of this ethological behavior through an anatomically distributed—but functionally modular—pattern of neural activity. [ABSTRACT FROM AUTHOR]

Objective: Type 2 diabetes mellitus (T2DM) over time predisposes to inflammatory responses and abnormalities in functional brain networks that damage learning, memory, or executive function. The hippocampus is a key region often reporting connectivity abnormalities in memory disorders. Here, we investigated peripheral inflammatory responses and resting-state functional connectivity (RSFC) changes characterized of hippocampal subregions in type 2 diabetes-associated cognitive decline (T2DACD). Methods: The study included 16 patients with T2DM, 16 patients with T2DACD and 25 healthy controls (HCs). Subjects were assessed for cognitive performance, tested for the expression of inflammatory factors IL-6, IL-10 and TNF-α in peripheral serum, underwent resting-state functional magnetic resonance imaging scans, and analyzed for RSFC using the hippocampal subregions as seeds. We also calculated the correlation between cognitive performance and RSFC of hippocampal subregion, and analyzed the significantly altered RSFC values of T2DACD for Receiver Operating Characteristic (ROC) analysis. Results: T2DACD patients showed a decline in their ability to complete cognitive assessment scales and experimental paradigms, and T2DM did not show abnormal cognitive performance. IL-6 expression was increased in peripheral serum in both T2DACD and T2DM. Compared with HCs, T2DACD showed abnormalities RSFC of the left anterior hippocampus with left precentral gyrus and left angular gyrus. T2DM showed abnormalities RSFC of the left middle hippocampus with right medial frontal gyrus, right anterior and middle hippocampus with left precuneus, left anterior hippocampus with right precuneus and right posterior middle temporal gyrus. Compared with T2DM, T2DACD showed abnormalities RSFC of the left posterior hippocampus and right middle hippocampus with left precuneus. In addition, RSFC in the left posterior hippocampus with left precuneus of T2DACD was positively correlated with Flanker conflict response time (r=0.766, P =0.001). In the ROC analysis, the significantly altered RSFC values of T2DACD achieved significant performance. Conclusions: T2DACD showed a significant decrease in attentional inhibition and working memory, peripheral pro-inflammatory response increased, and abnormalities RSFC of the hippocampal subregions with default mode network and sensory-motor network. T2DM did not show a significant cognitive decline, but peripheral pro-inflammatory response increased and abnormalities RSFC of the hippocampus subregions occurred in the brain. In addition, the left precuneus may be a key brain region in the conversion of T2DM to T2DACD. The results of this study may provide a basis for the preliminary diagnosis of T2DACD. [ABSTRACT FROM AUTHOR]

Background: Functional magnetic resonance imaging has been used in many studies to explore the neural mechanism of acupuncture in patients with post-stroke motor dysfunction. Inconsistent results have been found in these studies, however. This activation likelihood estimation (ALE) meta-analysis was designed to quantitatively integrate changes in brain activity and the neurological effects of acupuncture on patients with motor dysfunction after stroke. Methods: We searched PubMed, Embase, Web of Science, the Cochrane Library, China Science and Technology Journal Database, the China Biology Medicine, the China National Knowledge Infrastructure, and Wanfang Data Knowledge Service Platform for literature from the establishment of the database until March 21, 2024. Research papers were selected, data extracted, and quality assessment was done independently by two researchers. The GingerALE software was used for meta-analysis, and Jackknife sensitivity analysis was employed to assess result robustness. Results: We ended up analyzing 14 studies that included 235 patients and 100 healthy people. ALE meta-analysis showed that Compared with healthy people, the enhanced brain region in poststroke patients with motor dysfunction was located in the left posterior lobe of the cerebellum, the left inferior frontal gyrus, and the left precuneus (p < 0.001). After acupuncture, the activated regions were mainly located in the left posterior lobe of the cerebellum, the right lentiform nucleus putamen, the right medial frontal gyrus, the right inferior frontal gyrus, the left precuneus, the right middle temporal gyrus, the left claustrum, the left cerebellar tonsil, the right superior marginal gyrus, the inactivated area is located in the right medial frontal gyrus the left precentral gyrus and the right precuneus (p < 0.001). Conclusion: Acupuncture can reestablish motor function by causing extensive changes in the brain function of patients with stroke, which may be the neurological effect of acupuncture therapy on stroke patients. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024526263. [ABSTRACT FROM AUTHOR]

The hippocampus is a brain region that is essential for the initial encoding of episodic memories. However, the consolidation of these memories is thought to occur in the neocortex, under guidance of the hippocampus, over the course of days and weeks. Communication between the hippocampus and the neocortex during hippocampal sharp wave-ripple oscillations is believed to be critical for this memory consolidation process. Yet, the synaptic and circuit basis of this communication between brain areas is largely unclear. To address this problem, we perform in vivo whole-cell patch-clamp recordings in the frontal neocortex and local field potential recordings in CA1 of head-fixed mice exposed to a virtual-reality environment. In mice trained in a goal-directed spatial task, we observe a depolarization in frontal principal neurons during hippocampal ripple oscillations. Both this ripple-associated depolarization and goal-directed task performance can be disrupted by chemogenetic inactivation of somatostatin-positive (SOM+) interneurons. In untrained mice, a ripple-associated depolarization is not observed, but it emerges when frontal parvalbumin-positive (PV+) interneurons are inactivated. These results support a model where SOM+ interneurons inhibit PV+ interneurons during hippocampal activity, thereby acting as a disinhibitory gate for hippocampal inputs to neocortical principal neurons during learning. [ABSTRACT FROM AUTHOR]

Alpha oscillations are associated with various psychiatric disorders, with many studies focusing on the prefrontal cortex, where transcranial alternating current stimulation (TACS) is applied in the alpha frequency band. This approach often involves selecting individualized alpha frequencies to resonate with their endogenous alpha oscillations. While strong alpha oscillations (8–13 Hz) are typically induced when the eyes are closed, they can also occur during the resting state with eyes open. However, it remains unclear whether these alpha oscillations share a common neural generation mechanism. Exploring which of these alpha oscillations is more suitable as a stable alpha peak frequency is a question of significant interest. Therefore, to systematically study this issue, we specifically collected resting-state electroencephalographic (EEG) data from the prefrontal region of 40 individuals, under both eyes-open and closed- eye conditions, with multiple follow-ups extending up to nine months. Through spectral analysis on each person's entire dataset and averaging the results, we observed a significant positive correlation between the alpha-band power in the eyes-open and the eyes-closed states, in terms of both absolute power and relative power. Further analysis revealed that this correlation was primarily contributed by the periodic activity within the alpha band. Upon modelling the oscillatory components, we discovered distinct differences in the oscillatory characteristics-such as number of the alpha sub-oscillations between the eyes-open state and the eyes-closed state. Our study is the first to systematically explored the relationship between alpha oscillations in the prefrontal cortex in the eyes-open and eyes-closed states, identifying both shared part of the neural generation mechanism and some distinct neural mechanisms that are unique to each state. [ABSTRACT FROM AUTHOR]

A new case of dementia is diagnosed every 3 s. Beyond age, risk prediction of dementia is challenging. There is growing evidence of underlying processes that connect aging across organ systems and may provide insight for early detection, and there is a need to identify early biomarkers at an age when action can be taken to mitigate cognitive decline. We hypothesized that timing of menopause, a marker of ovarian aging, predicts brain age decades later. We used 2086 subjects with multiple “omics” measurements from post‐mortem brain samples. Age at menopause (AAM) is positively correlated with cognitive function and negatively correlated with pre‐frontal cortex aging acceleration (calculated as estimated biological age from DNA methylation minus chronological age). Genetic correlations showed that at least part of these associations is derived from shared heritability. To dissect the mechanism linking AAM to cognitive decline, we turned to transcriptomic data which confirmed that later AAM was associated with gene expression in pre‐frontal cortex consistent with better cognition, and among those who reached menopause naturally, decreased gene expression of pathways implicated in aging. Those with surgical menopause displayed different molecular changes, including perturbed nicotinamide adenine dinucleotide (NAD+) activity, validated by metabolomics. Bile acid metabolism was perturbed in both groups, although different bile acid ratios were associated with AAM in each. Together, our data suggest that AAM is predictive of brain aging and cognition, with potential mediation by the gut, although through different mechanisms depending on the type of menopause. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder with a higher risk incidence in females than in males, and there are also differences in AD pathophysiology between sexes. The role of sex in the pathogenesis of AD may be crucial, yet the cellular and molecular basis remains unclear. Here, we performed a comprehensive analysis using four public transcriptome datasets of AD patients and age‐matched control individuals in prefrontal cortex, including bulk transcriptome (295 females and 402 males) and single‐nucleus RNA sequencing (snRNA‐seq) data (224 females and 219 males). We found that the transcriptomic profile in female control was similar to those in AD. To characterize the key features associated with both the pathogenesis of AD and sex difference, we identified a co‐expressed gene module that positively correlated with AD, sex, and aging, and was also enriched with immune‐associated pathways. Using snRNA‐seq datasets, we found that microglia (MG), a resident immune cell in the brain, demonstrated substantial differences in several aspects between sexes, such as an elevated proportion of activated MG, altered transcriptomic profile and cell–cell interaction between MG and other brain cell types in female control. Additionally, genes upregulated in female MG, such as TLR2, MERTK, SPP1, SLA, ACSL1, and FKBP5, had high confidence to be identified as biomarkers to distinguish AD status, and these genes also interacted with some approved drugs for treatment of AD. These findings underscore the altered immune response in female is associated with sex difference in susceptibility to AD, and the necessity of considering sex factors when developing AD biomarkers and therapeutic strategies, providing a scientific basis for further in‐depth studies on sex differences in AD. [ABSTRACT FROM AUTHOR]